Polymorph of acid4-[2-[4-[1-(2-ethoxyethyl)-1h-benzimidazole-2-1l]-1piperidinyl]ethyl]-$g(a), $g(a)-dimetiiyl-benzeneacetic

ABSTRACT

Polymorph 1 of 4-[2-[1-(2-ethoxyethyl)-1H-benzidimazole-2-yl]-1-piperidinyl]ethyl]-αα-dimethyl-benzenoacetic acid of formula (I) is described, procedures for its preparation, pharmaceutical formulae containing polymorph 1 and the use of polymorph 1 to treat allergic reactions and pathological processes mediated by histamine in mammals such as man.

AREA OF THE INVENTION

The invention refers to a new polymorphous crystalline form of4-[2-[1-(2-ethoxyethyl)-1H-benzidimazole-2-yl]-1-piperidinyl]ethyl]-αα-dimethyl-benzeno-aceticacid (herein referred to as “bilastin”) of formula (I).

From hereon referred to as polymorph 1, to procedures used to prepareit, to pharmaceutical formulae that contain polymorph 1 and to the useof polymorph 1 to treat allergic reactions and pathological processesmediated by histamine in mammals, such as man.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 5,877,187 confers the rights to bilastin, a preparationwith antihistaminic properties without sedative or cardiovasculareffects. This patent also concerns a procedure to prepare bilastin andthe use of this preparation to treat allergic reactions in mammals butit does not include or suggest the possible existence of polymorphicforms of this compound.

To prepare pharmaceutical preparations containing bilastin for theiradministration in mammals and especially in man, in accordance withinternational health authority specifications, bilastin must bemanufactured in the most stable crystalline form possible, especially ina form that has constant physical properties.

SUMMARY OF THE INVENTION

We have found that bilastin can exist in three different crystallinepolymorphic forms, each with different physical properties.

The invention refers to a pure crystalline form of polymorph 1 ofbilastin, characterised by X-ray chromatographic analysis, withapproximate crystal parameters as follows: Crystallograph systemMonoclinical Spatial group P2 (1)/c Crystal size 0.56 × 0.45 × 0.24 mmCell dimension a = 23.38 (5) A angstrom α = 90° b = 8.829 (17) A β = 90°c = 12.59 (2) A γ = 90° Volume 2600 A³ Z, calculated density 4, 1.184mg/m³

The crystalline polymorph 1 of bilastin is also characterised by itsinfrared absorption spectrum in potassium bromide tablet that has thefollowing characteristic absorption bands, expressed in reciprocalcentimetres:

3430 (s)*; 3057 (w)*; 2970 (s); 2929 (s); 2883 (m)*; 2857 (m); 2797 (w);1667 (m); 1614 (m); 1567 (w); 1509 (s); 1481 (m); 1459 (vs)*; 1431 (m);1378 (w); 1346 (m); 1326 (m); 1288 (w); 1254 (m); 1199 (w); 1157 (w);1121 (vs); 1045 (w); 1020 (w); 1010 (w); 991 (w); 973 (w); 945 (w); 829(w); 742 (s); 723 (w); 630 (w), * where (w)=weak intensity, (m)=mediumintensity, (s)=strong intensity, (vs)=very strong intensity. FIG. 1represents the infrared spectrum of the crystalline polymorph 1 of thebilastin in a potassium bromide tablet recorded in a Fourier PerkinElmer Spectrum One transformer spectrophotometer.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows a typical infrared absorption spectrum in potassium bromideof polymorph 1. (Vertical axis: Transmission (%); Horizontal axis: Bandnumber (cm⁻¹)).

FIG. 2 shows a typical infrared absorption spectrum in potassium bromideof polymorph 2. (Vertical axis: Transmission (%); Horizontal axis: Bandnumber (cm⁻¹)).

FIG. 3 shows a typical infrared absorption spectrum in potassium bromideof polymorph 3. (Vertical axis: Transmission (%); Horizontal axis: Bandnumber (cm⁻¹)).

DETAILED DESCRIPTION OF THE INVENTION

We have found that bilastin can exist in three clearly differentpolymorphic forms called polmorph 1, polymorph 2 and polymorph 3.

The procedure described in U.S. Pat. No. 5,877,187 generates a mixtureof polymorphs 2 and 3. We have discovered experimental conditions andspecific solvents to produce clearly different polymorphic forms ofbilastin. The crystalline polymorph 1 of pure bilastin is preparedaccording to the procedures of this invention. The polymorphic forms 1and 2 are stable. Polymorph 3 is not very stable and is difficult toobtain in the pure form. Both polymorph 2 and polymorph 3 are convertedinto polymorph 1 for the purposes of this invention.

Polymorph 1 of bilastin has a melting point of 200.3° C. Polymorph 2 hasa melting point of 205.2° C. Polymorph 3 has a melting point of 197.0°C.

The crystalline polymorphic form 1 of bilastin is also characterised byits infrared absorption spectrum in potassium bromide that has thefollowing characteristic absorption bands, expressed in reciprocalcentimetres:

3430 (s)*; 3057 (w)*; 2970 (s); 2929 (s); 2883 (m)*; 2857 (m); 2797 (w);1667 (m); 1614 (m); 1567 (w); 1509 (s); 1481 (m); 1459 (vs)*; 1431(m);1378 (w); 1346 (m); 1326 (m); 1288 (w); 1254 (m); 1199 (w); 1157(w); 1121 (vs); 1045 (w); 1020 (w); 1010 (w); 991 (w); 973 (w); 945 (w);829 (w); 742 (s); 723 (w); 630 (w), * where (w)=weak intensity,(m)=medium intensity, (s)=strong intensity, (vs)=very strong intensity.FIG. 1 represents the infrared spectrum of the crystalline polymorph 1of the bilastin in a potassium bromide tablet recorded in a FourierPerkin Elmer Spectrum One transformer spectrophotometer.

The crystalline polymorphic form 2 of bilastin is also characterised byits infrared absorption spectrum in potassium bromide that has thefollowing characteristic absorption bands, expressed in reciprocalcentimetres:

3429 (s)*; 3053 (w)*; 2970 (s)*; 2932 (s); 2868 (s); 2804 (w); 1699 (m);1614 (m)*; 1567 (m); 1508 (s); 1461 (vs)*; 1381 (m); 1351 (s); 1331 (m);1255 (m); 1201 (w); 1156 (m); 1121 (vs); 1048 (w); 995 (w); 823 (w); 767(w); 744 (s); 724 (d); 630 (w), * where (w)=weak intensity, (m)=mediumintensity, (s)=strong intensity, (vs)=very strong intensity. FIG. 2represents the infrared spectrum of the crystalline polymorph 2 ofbilastin in a potassium bromide tablet recorded in a Fourier PerkinElmer Spectrum One transformer spectrophotometer.

The crystalline polymorphic form 3 of bilastin is also characterised byits infrared absorption spectrum in potassium bromide that has thefollowing characteristic absorption bands, expressed in reciprocalcentimetres:

3430 (s)*; 3053 (w)*; 2970 (s); 2932 (s); 2868 (s); 2804 (w); 1921 (w);1708 (m)*; 1614 (m); 1568 (m); 1508 (s); 1461 (vs)*; 1380 (m); 1351 (m);1330 (m); 1271 (m); 1255 (m), 1201 (w); 1156 (m); 1121 (vs); 1048 (w);995 (w); 823 (m); 767 (w); 744 (s); 724 (w); 630 (w), * where (w)=weakintensity, (m)=medium intensity, (s)=strong intensity, (vs)=very strongintensity. FIG. 3 represents the infrared spectrum of the crystallinepolymorph 3 of the bilastin in a potassium bromide tablet recorded in aFourier Perkin Elmer Spectrum One transformer spectrophotometer.

We have discovered that, in selected experimental conditions, themixture of the polymorphic forms 2 and 3, obtained according to U.S.Pat. No. 5,877,187, is surprisingly transformed into polymorph 1. Wehave also discovered that polymorph 1 of bilastin is very stable and isnot transformed into any of the other polymorphs 2 and 3. Similarly, inthe same experimental conditions, the pure polymorphic form 2 ofbilastin is surprisingly transformed into the pure polymorphic form 1.Polymorphic form 3, which is the most unstable, undergoes the sametransformation in the same conditions.

Polymorph 1 of bilastin is a very stable polymorph at room temperatureand is, therefore, very useful as an active ingredient of apharmaceutical preparation. Polymorph 1 is also stable when stored at,temperatures above room temperature.

The polymorphic crystalline form 1 of bilastin is characterised by thefollowing data of its X-ray crystallographic analysis as a monocrystal,with crystal parameters of approximately the following values:Crystallograph system Monoclinical Spatial group P2 (1)/c Crystal size0.56 × 0.45 × 0.24 mm Cell dimension a = 23.38 (5) A angstrom α = 90° b= 8.829 (17) A β = 90° c = 12.59 (2) A γ = 90° Volume 2600 A³ Z,calculated density 4, 1.184 mg/m³

During the development of polymorph 1 of bilastin for pharmaceuticalpreparations, elaborated according to correct manufacturing procedures,we have discovered that crystallization of bilastin (prepared accordingto the description given in U.S. Pat. No. 5,877,187) of short chainedalcohols, preferably isopropylic alcohol and n-butanol and its mixtures,leads to generation of the pure polymorphic form 1 of bilastin with ahigh yield. Crystallisation of acetone, dimethylsulphoxide,dimethylformamide, acetonitrile and tetrahydrofurane or its mixturesalso lead to generation of polymorph 1, although with lower yields. Itis, therefore, preferable to use the former solvents.

The infrared spectrum of polymorph 1 of bilastin in potassium bromide ischaracterised by the following bands, absent from polymorphs 2 and 3:

Wavelength (cm⁻¹)

3057

2929

2883

2857

2797

1667

1481

1431

1346

1326

1288

973

945

829

FIG. 1 shows the complete infrared spectrum of polymorph 1 of bilastinin potassium bromide, recorded with a Fourier Perkin Elmer Spectrum Onetransformer spectrophotometer.

Pharmaceutical Preparations

Pharmaceutical preparations of this invention can contain, as well as aneffective quantity of polymorph 1 of bilastin as an active ingredient asan antiallergic or antihistaminic agent, several pharmaceuticallyacceptable excipients that can be solid or liquid. The solidpharmaceutical preparations include powders, tablets, dispersiblegranules, capsules, stamps and suppositories. A solid excipient can beone of several substances that act as diluents, aromatising agents,agglutinants or disintegrating agents and an encapsulation material. Thepowders and tablets preferentially contain from approximately 5 toapproximately 20 per cent of the active ingredient. Appropriate solidexcipients are magnesium carbonate, magnesium stearate, talc, sugar,lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose,sodium carboxymethylcellulose, waxes with low melting point, cocoabutter and similar products. The term “preparations” includes theformulation of the active ingredient with an excipient for encapsulationto produce a capsule in which the active ingredient (with or withoutother excipients) is surrounded with the excipient by an encapsulationmaterial. Tablets, powders, stamps and capsules can be used as suitableforms for oral administration. The active ingredient can also beincorporated into a chewing gum that can contain sweeteners, flavoringsand colorings as appropriate.

To prepare suppositories, a compound with a low melting point, such as amixture of fatty acid glycerides or cocoa butter, is melted and theactive ingredient is mixed well and homogeneously dispersed in themixture. The homogeneous melted mixture is placed in the appropriatemoulds and left to cool until it solidifies.

Liquid preparations include suspensions, lotions and emulsions. Anexample of these corresponds to aqueous suspensions that can be made bymixing the finely divided active ingredient in water with suspensionagents. Aqueous solutions can be prepared by placing the activeingredient in water and adding suitable coloring agents, aromas,stabilising agents, sweeteners, solubilising and thickening agents asappropriate.

Also, topical preparations are considered for nasal, ophthalmic anddermal use. Appropriate formulae for nasal administration can correspondto solutions or suspensions. Ophthalmic formulae can be lotions,suspensions or ointments. Dermal preparations can be lotions,suspensions, ointments and creams. Ointments usually contain lipophylicexcipients such as mineral oil or vaseline. Solutions for ophthalmic usecan contain sodium chloride, acid and/or base to adjust the pH, andpurified water and preservatives.

Similarly, a compound is being contemplated for transdermic use,consisting of a therapeutically effective amount of active ingredientincorporated into an excipient that corresponds to a liquid, a gel, asolid matrix or an adhesive patch sensitive to pressure, to be releasedvia a transdermic administration system.

The effective antiallergic or antihistaminic amount of polymorph 1 ofbilastin for topical administration varies between 0.1 and 5% of thetotal weight of the pharmaceutical compound. The preferred amount rangesfrom 0.1 to 2% of the total weight of the pharmaceutical compound.

The effective antiallergic or antihistaminic amount of polymorph 1 ofbilastin for oral administration varies from 1 to 50 mg/day, withpreferably an amount corresponding to approximately 2 to 20 mg/day in asingle or fractionated doses.

Polymorph 1 of bilastin has antihistaminic properties that have beendemonstrated in experimental pharmacological models, such as preventinghistamine-induced lethality in the guinea-pig and antagonism againstcutaneous capillary permeability induced by histamine in the rat.

The following examples illustrate but do not limit the scope of thepresent invention.

EXAMPLE 1

Preparation of Polymorph 1 of Bilastin

Dissolve bilastin (see the U.S. Pat. No. 3,877,187) in isopropylicalcohol heated to reflux for approximately 15-20 minutes under nitrogenwhile stirring. Cool the solution to 50° C. over 6 hours and stopstirring. Let the solution cool to room temperature and stir again forthree hours, filter and wash with cold isopropylic alcohol. Dry thesolid residue in a vacuum cabinet at 35-40° C. to constant weight.

EXAMPLE 2

Preparation of Polymorph 1 of Bilastin

Heat a suspension of bilastin (see U.S. Pat. No. 5,877,187) in n-butanoland reflux for 3 hours under nitrogen while stirring. Leave the solutionto cool while stirring, filter off the solid residue and dry it in avacuum chamber at 35-40° C. to constant weight.

EXAMPLE 3

Preparation of Polymorph 1 of Bilastin

Treat a mixture of polymorphs 2 and 3 of bilastin for several hours withhot acetone. Let the mixture cool to room temperature and filter off thesolid residue. Dry it to constant weight.

EXAMPLE 4

Preparation of Polymorph 1 of Bilastin

Dissolve polymorph 3 of bilastin in isopropylic alcohol heated to refluxand stir for approximately 15-20 minutes under nitrogen. Let thesolution reach room temperature constantly stirring, filtering andwashing with cold isopropanol. Dry the solid in a vacuum chamber at35-40° C. to constant weight.

EXAMPLE 5

Preparation of Polymorph 1 of Bilastin

Dissolve polymorph 2 of bilastin in n-butanol heated to reflux whilestirring for approximately 3 hours. Let the solution reach roomtemperature while stirring, filtering and draining. Dry the solid in avacuum chamber at 35-40° C. to constant weight.

1. Polymorph 1 of bilastin having, upon X-ray crystallography analysis,crystal parameters of substantially the following: Crystallograph systemMonoclinical Spatial group P2 (1)/c Crystal size 0.56 × 0.45 × 0.24 mmCell dimension a = 23.38 (5) A angstrom α = 90° b = 8.829 (17) A β = 90°c = 12.59 (2) A Y = 90° Volume 2600 A³ Z, calculated density 4, 1.184mg/m³


2. The Polymorph 1 of bilastin according to claim 1, wherein saidPolymorph 1 has an infrared spectrum in potassium bromide with thefollowing bands: Wavelength (cm⁻¹) 3057 2929 2883 2857 2797 1666 14811431 1346 1326 1288 973 945 829
 3. The Polymorph 1 of bilastin accordingto claim 1, wherein said Polymorph 1 has an infrared spectrum inpotassium bromide which is substantially identical to that shown inFIG.
 1. 4. A process for preparing the Polymorph 1 of bilastin accordingto claim 1, wherein said process comprises heating bilastin in a solventselected from the group consisting of short chain alcohols, acetone andmixtures thereof.
 5. A process for preparing the Polymoph 1 of bilastinaccording to claim 1, wherein said process comprises heating polymorphs2 and 3 of bilastin or a mixture thereof, in a solvent selected from thegroup consisting of short chain alcohols, acetone and mixtures thereof.6. A method for obtaining at least one of an antihistaminic and anantiallergenic effect in a subject in need thereof, which methodcomprises administering to said subject a sufficient amount of thePolymorph 1 of bilastin according to claim 1 to produce said effect. 7.A method for obtaining at least one of an antihistaminergic and anantiallergic effect in a subject in need thereof, which method comprisesadministering to said subject a sufficient amount of the Polymorph 1 ofbilastin according to claim 2 to produce said effect.
 8. A method ofobtaining at least one of an antihistaminergic and an antiallergiceffect in a subject in need thereof, which method comprisesadministering to said subject a sufficient amount of the Polymorph 1 ofbilastin according to claim 3 to produce said effect.
 9. Apharmaceutical preparation comprising an effective amount of thePolymorph 1 of bilastin according to claim 1 and an acceptablepharmaceutical excipient.
 10. A pharmaceutical preparation comprising aneffective amount of the Polymorph 1 of bilastin according to claim 2 andan acceptable pharmaceutical excipient.
 11. A pharmaceutical preparationcomprising an effective amount of the Polymorph 1 of bilastin accordingto claim 3 and an acceptable pharmaceutical excipient.
 12. A method forpreparing a medicinal product for treating allergic reactions andpathological processes mediated by histamine, said method comprisingincorporating within a medicinal product an amount of the Polymorph 1 ofbilastin according to claim 1 effective to treat said allergic reactionsand pathological processes mediated by histamine.
 13. A method forpreparing a medicinal product for treating allergic reactions andpathological processes mediated by histamine, said method comprisingincorporating within a medicinal product an amount of the Polymorph 1 ofbilastin according to claim 2 effective to treat said allergic reactionsand pathological processes mediated by histamine.
 14. A method forpreparing a medicinal product for treating allergic reactions andpathological processes mediated by histamine, said method comprisingincorporating within a medicinal product an amount of the Polymorph 1 ofbilastin according to claim 3 effective to treat said allergic reactionsand pathological processes mediated by histamine.
 15. A process forpreparing the Polymorph 1 of bilastin according to claim 2, wherein saidprocess comprises heating bilastin in a solvent selected from the groupconsisting of short chain alcohols, acetone and mixtures thereof.
 16. Aprocess for preparing the Polymorph 1 of bilastin according to claim 3,wherein said process comprises heating bilastin in a solvent selectedfrom the group consisting of short chain alcohols, acetone and itsmixtures thereof.
 17. A process for preparing the Polymorph 1 ofbilastin according to claim 2, wherein said process comprises heatingpolymorphs 2 and 3 of bilastin or a mixture thereof, in a solventselected from the group consisting of short chain alcohols, acetone andmixtures thereof.
 18. A process for preparing the Polymorph 1 ofbilastin according to claim 3, wherein said process comprises heatingpolymorphs 2 and 3 of bilastin or a mixture thereof, in a solventselected from the group consisting of short chain alcohols, acetone andmixtures thereof.
 19. The process of claim 4, wherein the short chainalcohol is at least one of isopropylic alcohol and n-butanol.
 20. Theprocess of claim 5, wherein the short chain alcohol is at least one ofisopropylic alcohol and n-butanol.
 21. The process of claim 15, whereinthe short chain alcohol is at least one of isopropylic alcohol andn-butanol.
 22. The process of claim 16, wherein the short chain alcoholis at least one of isopropylic alcohol and n-butanol.
 23. The process ofclaim 17, wherein the short chain alcohol is at least one of isopropylicalcohol and n-butanol.
 24. The process of claim 18, wherein the shortchain alcohol is at least one of isopropylic alcohol and n-butanol.